Thyroid hormone drugs are used to treat thyroid hormone deficiency and thyroid hormone replacement therapy in mammals, for example, humans and dogs. In treatment of thyroid hormone deficiency very low daily doses of levothyroxine sodium are used in the range from 25 to 300 mcg. Due to its high potency, it is very important to avoid dosage variations as this may cause serious symptoms of hypothyroidism such as severe depression, fatigue, weight gain, constipation, cold intolerance, swelling, and difficulty concentrating, if levothyroxine sodium is under dosed, or of hyperthyroidism, such as pain, heart palpitations, or cardiac arrhythmias, if levothyroxine sodium dose is too high. Thyroid hormone drugs like levothyroxine or salts thereof are known for its poor stability. Such poorly stable or fast degradation prone drugs may lose its potency over the period of shelf life which may result in under-dosing. Also, there is a common practice to add overages in order to compensate probable potency loss. All such variations of under-dosing or over-dosing of the drug may result in undesirable clinical outcomes. Therefore, storage stability and content uniformity of levothyroxine or salts thereof in the pharmaceutical preparations is a critical issue.
Hypothyroidism is a common condition. It has been reported in the United States Federal Register that hypothyroidism has a prevalence of 0.5 percent to 1.3 percent in adults. In people over 60, the prevalence of primary hypothyroidism increases to 2.7 percent in men and 7.1 percent in women. Because congenital hypothyroidism may result in irreversible mental retardation, which can be avoided with early diagnosis and treatment, newborn screening for this disorder is mandatory in North America, Europe, and Japan.
Thyroid hormone replacement therapy can be a chronic, lifetime endeavor. The dosage is established for each patient individually. The goal of therapy is to achieve and maintain a clinical and biochemical euthyroid state. The goal of suppressive therapy is to inhibit growth and/or function of abnormal thyroid tissue. The dose of levothyroxine sodium tablets, that is adequate to achieve treatment goals depends on a variety of factors including the patient's age, body weight, cardiovascular status, concomitant medical conditions, including pregnancy, concomitant medications, and the specific nature of the condition being treated. Dosing must be individualized and adjustments made based on periodic assessment of the patient's clinical response and laboratory parameters. Generally, the initial dose is small. The amount is increased gradually until clinical evaluation and laboratory tests indicate that an optimal response has been achieved. The dose required to maintain this response is then continued. It has been reported that the dosage increase should be very gradual in patients with myxedema or cardiovascular disease to prevent precipitation of angina, myocardial infarction, or stroke.
Hyperthyroidism is a known risk factor for osteoporosis. Several studies suggest that sub clinical hyperthyroidism in premenopausal women receiving thyroid hormone drugs for replacement or suppressive therapy is associated with bone loss. To minimize the risk of osteoporosis, it is preferable that the dose be kept to the lowest effective dose.
Because of the risks associated with over-treatment or under-treatment with thyroid hormone drug, there is a need for thyroid hormone products that are consistent in potency, bioavailability, and content uniformity. Such consistency is best accomplished by manufacturing techniques that maintain consistent amounts of the active moiety in compositions during its manufacturing process.
Thyroid hormone drugs are natural or synthetic preparations containing tetraiodothyronine (T4, levothyroxine) or triiodothyronine (T3, liothyronine) or both, usually as their pharmaceutically acceptable (e.g., sodium) salts. T4 and T3 are produced in the human thyroid gland by the iodination and coupling of the amino acid tyrosine. T4 contains four iodine atoms and is formed by the coupling of two molecules of diiodotyrosine (DIT). T3 contains three atoms of iodine and is formed by the coupling of one molecule of DIT with one molecule of monoiodotyrosine (MIT). Both hormones are stored in the thyroid colloid as thyroglobulin. Thyroid hormone preparations belong to two categories: (1) natural hormonal preparations derived from animal thyroid, and (2) synthetic preparations. Natural preparations include desiccated thyroid and thyroglobulin.
Desiccated thyroid is derived from domesticated animals that are used for food by man (either beef or hog thyroid), and thyroglobulin is derived from thyroid glands of the hog. The United States Pharmacopoeia (USP) has standardized the total iodine content of natural preparations. Thyroid USP contains not less than (NLT) 0.17 percent and not more than (NMT) 0.23 percent iodine, and thyroglobulin contains not less than (NLT) 0.7 percent of organically bound iodine. Iodine content is only an indirect indicator of true hormonal biologic activity.
Synthetic forms for both T4 and T3 thyroid hormones are available from a number of manufacturers. For example, liothyronine sodium (T3) tablets are available under the trademark Cytomel from King Pharmaceuticals, Inc., St. Louis, Mo. Levothyroxine sodium (T4) is available under the trade name Levoxyl® from King Pharmaceuticals, Inc., under the trade name Synthroid® from Abbvie Inc. Chicago, and under the trade name Unithroid® from Jerome Stevens Pharmaceuticals, Bohemia, N.Y. In addition, a veterinarian preparation of levothyroxine sodium is available under the trade name Soloxine® from King Pharmaceuticals, Inc.
It is well known that the stability of thyroid hormone drugs is quite poor. Also thyroid hormone drugs are hygroscopic and are susceptible to degradation in the presence of moisture, oxygen, and/or light, and under conditions of high temperature. The instability is especially notable in the presence of pharmaceutical excipients, such as carbohydrates, including sucrose, dextrose, and starch, as well as certain dyes. The critical nature of the dosage requirements, and the lack of stability of the active ingredients in the popular pharmaceutical formulations, has led to a crisis which has adversely affected the most prescribed thyroid drug products. See, e.g., 62 Fed. Reg. 43535 (Aug. 14, 1997).
It is desirable, therefore, to prepare stabilized pharmaceutical compositions of thyroid hormone drugs which will have a longer shelf life and reduce the risk associated with degradation products that can be used effectively in the treatment of thyroid hormone deficiency in humans or animals.
U.S. Pat. No. 5,225,204 is directed to improving the stability of levothyroxine sodium. In one embodiment the patent discloses the preparation of stabilized levothyroxine sodium in a dry state by mixing levothyroxine sodium with a cellulose tableting agent using geometric dilution and subsequently combining this mixture with the same or a second cellulose tableting agent, such as microcrystalline cellulose.
U.S. Pat. No. 6,555,581 describes a stabilized immediate release pharmaceutical composition of levothyroxine essentially devoid of carbohydrates. The compositions lose up to 0.3% potency per month during 18 month stability period.
U.S. Pat. No. 7,067,148 describes a stable immediate release pharmaceutical composition of levothyroxine essentially free of carbohydrates wherein the compositions do not lose potency up to about 12.6% w/w during 18 month stability period.
U.S. Pat. No. 5,958,979 describes stabilization of thyroxine preparations by addition of sodium thiosulfate. However, the use of substances like sodium thiosulfate in pharmaceutical preparations is undesirable from the toxicological point of view.
International (PCT) Publication No. WO 99/59551 describes the improvement of storage stability of levothyroxine sodium containing solid pharmaceutical preparations by using gelatin as a binder. As described in the introduction such stabilized formulation has been developed in order to meet the increased requirements on stability as established by the Food and Drug Administration (FDA) in 1996. According to such FDA requirements levothyroxine sodium degradation in tablets throughout their shelf life has been fixed to 10% at the most.
Patel et al. examined the effect of various pH modifying additives on the stability of levothyroxine sodium tablets (Patel H. et al: The effect of excipients on stability of levothyroxine sodium pentahydrate tablets, Int J Pharm 264 (2003) 35-43). It was found that the basic pH modifying additives, sodium carbonate, sodium bicarbonate and magnesium oxide led to improvement of the stability of levothyroxine sodium tablets, whereas acid pH modifying additives, tartaric acid and citric acid led to impairment of stability.
U.S. Pat. No. 8,293,272 discloses stabilized pharmaceutical preparations containing levothyroxine sodium by adjusting the water activity of preparations to values below 0.4. The patent teaches the need to convert levothyroxine pentahydrate form to more stable tetrahydrate form by using specialized drying process. Consequently, the product formulation process becomes lengthy and time consuming. Also, the water activity of the formulation varies with the change of relative humidity during shelf life so that additional measures need to be taken, such as moisture-tight packs, which result in additional costs.
Also, thyroid hormone drugs are hygroscopic and are susceptible to degradation in the presence of moisture, oxygen, and/or light, and under conditions of high temperature. Such degradation of active ingredients results in potency loss which may lead to inadequate dosing. In certain situations, due to poor stability performance, manufacturers released final drug product with a stability “overage” (i.e., more than 100% of the labeled claim) to address the rapid degradation of the product and to allow a practical shelf life meeting desired potency specifications. Such practice also raised concerns of both safety and effectiveness for such products. Thus, there is a need for storage stable pharmaceutical compositions which can maintain the potency of the drug during shelf life thereby avoid the need to add any overages to compensate the potency loss due to such instability problem.
In 2007, the FDA raised the stability requirements on levothyroxine sodium containing products to further diminish the risk associated with degradants generated during shelf life. The limit of levothyroxine sodium degradation in tablets was lowered from 10% to 5% (FDA press release from Oct. 3, 2007).
Thyroid hormone drugs are highly potent drugs. Drugs like levothyroxine are approved at very tow doses of 25 mcg, 50 mcg, 75 mcg, 88 mcg, 112 mcg, 125 mcg, 137 mcg, 150 mcg, 175 mcg, 200 mcg, and 300 mcg for treating thyroid related problems. Also, levothyroxine is needed to be prescribed and administered depending upon the individuals problem need, in order to fulfill an individual's dosing requirements, commercially available tablet dosage forms are provided with a break-line so as to divide the tablet in two or more equal parts. In case of such a potent low dose drug, if the drug is not uniformly distributed throughout the tablet then there will always be a chance that one part may have higher amount of drug than the other part. This may result in either under-dosing or over-dosing of the active ingredients resulting either in sub-therapeutic effects or side and/or toxic effects. Both under-dosing and over-dosing can have deleterious health impacts. In the case of under-dosing, a sub-optimal response and hypothyroidism could result. Under-dosing has also been reported to be a potential factor in decreased cardiac contractility and increased risk of coronary artery disease. Conversely, the over-dosing may result in toxic manifestations of hyperthyroidism such as cardiac pain, palpitations, or cardiac arrhythmia's. In patients with coronary heart disease, even a small increase in the dose of levothyroxine sodium may be hazardous in a particular patient. Thus, content uniformity and uniform distribution of the drug throughout the dosage form is of paramount importance.
There is an ongoing demand for thyroid hormone drug pharmaceutical compositions having an improved stability and content uniformity. The pharmaceutical compositions should ensure uniform drug distribution throughout the formulation, should not comprise any toxicologically unacceptable adjuvants, and should be capable of storage in a stable manner over an extended period of time.